Human papillomavirus (HPV), a sexually transmitted infection, is strongly associated with invasive cervical, vulvar, and anal cancers in women, and penile and anal cancers in men. Internationally, the incidence of cervical cancer varies greatly, with high rates observed in Mexico and low rates observed in the US and Europe. In the US, Hispanic women have significantly elevated rates of disease compared with non-Hispanic whites. The sexual behavior of the male partner may be as or more important than a Hispanic or Mexican woman's personal sexual behavior in predicting her risk of HPV infection and cervical disease. Unfortunately, little is known regarding the prevalence, incidence, and clearance of HPV infections in men, hampering efforts to control infection in both men and women. We propose to conduct a large binational (US-Mexico) prospective study of men, the HPV in Men Study (HIM). The goal of this revised application is to further our understanding of the natural history of HPV infection in men so that effective programs can be developed to reduce HPV disease burden in both men and women. Specifically, our aims are to enroll a cohort of 3000 men who will be examined every six months for four years, determine the incidence and persistence of type-specific penile HPV infections, the humoral immune response to HPV infection, and assess the factors independently associated with acquisition, persistence, and clearance of type-specific HPV infections in men. We hypothesize that HPV infection type distribution in men differs by country, that most infections in men are transient, and that type-specific HPV antibody response occurs only among persistently positive men. In addition, we hypothesize that current condom use and circumcision confers reduced risk of incident HPV infection, and that other sexually acquired infections increase risk. Our proposed study is unique in that it will prospectively assess HPV infection in a large cohort of men in the US and Mexico, representing countries of high and low risk. The study is timely in that it will yield information on types of male infection and incidence of infection necessary to design vaccine efficacy studies in men. It is cost-effective, operating in Mexico with a significantly reduced cost per participant enrolled compared to the US, enrolling men representative of both countries, and partnering with industry to significantly reduce HPV genotyping costs.